This invention relates to a novel and useful composition of matter. More particularly, the invention pertains to a pharmaceutical composition comprising polymerized cross-linked, stromal-free hemoglobin admixed with a pharmaceutically acceptable carrier. The polymerized crosslinked, stomal-free hemoglobin possesses valuable therapeutic utility as a blood substitute for transporting and supplying oxygen to vital tissues and organs and as a blood plasma expander for the management of disease and for maintaining circulatory integrity.
A critical and continual need exists for a therapeutic agent useful as a blood substitute for carrying and supplying oxygen and as a blood plasma expander. The need for the blood substitute exists for replacing blood lost by acute hemorrhage, to replace blood losses occurring during surgical operations, in resuscitation procedures after accidental blood loss, for supplying oxygen, and generally to maintain blood volume in related conditions. The need exists for a plasma expander in volume deficiency shock, as an alleviant in anaphylactic and allergic shock, for replacing plasma lost after burns and as a result of diarrhea.
Heretofore, an intense research effort was made and many materials were developed that could lend themselves for possible use as a plasma substitute and as a plasma expander. Generally, these materials are crystalloid solutions or colloidal-like polymeric solutions. The crystalloid materials include saline, compositions of saline and glucose, Hartmann's solution, and Ringer's solution. The colloidal-like polymer materials include pectin, gelatin, albumin, hydroxyethyl starch poly-(vinyl pyrrolidone), dextran and cellulose derivatives.
Similarly, attempts were made to develop materials that could be used as a blood substitute for supplying oxygen to body tissues and organs. These materials include synthetic substitutes for the oxygen carrying pigment hemoglobin such as artificial cells made of an oxygen permeable membrane enclosing an aqueous solution of hemoglobin, oxygen carrying coordination compounds of heme and imidazole, fluorocarbons, and water-soluble bis-histidino-cobalt complexes. Additionally, isolated hemoglobin and whole blood or red cells in physiological media have been used as blood substitutes.
While the above materials represent a contribution to the medical science, serious disadvantages are associated with these materials which restrict their use. For example, while the crystalloid solutions have the required osmolality, their use is limited as they neither supply the colloids needed in a volume replacement regimen, nor do they possess the ability for transporting and supplying oxygen. The colloid-polyelectrolyte solutions, while they possess the desired osmolality, are unacceptable because they lack hemostatic properties and are devoid of the ability to transport and deliver oxygen. Similarly, the use of synthetic substitutes is associated with disadvantages. For instance, the coordination compounds of heme and imidazole quickly lose their ability to combine with oxygen in biological fluids, and the water soluble compound, bishistidino-cobalt, absorbs oxygen reversibly, for a short period of one hour at 37.degree. C. The fluorocarbons are removed by the circulatory system as foreign substances, and they become lodged in the liver, spleen and other tissues. Artificial cells made of a membrane encapsulated hemoglobin have not been used for many reasons. For example, the use of microcapsules made from synthetic polymers such as polystyrene, ethyl cellulose, and silicon rubber introduces biologically incompatible materials into a living system. The cell wall of the capsules tend to leak, it is difficult to control permeability of the wall, and these capsules are too rigid and too large to pass through the capillary bed. The use of blood and blood fractions also is fraught with disadvantages. For example, the use of whole blood often is accompanied with the risk of transmission of hepatitis-producing virus which complicates the patient's recovery. Additionally, the use of whole blood requires blood-typing and cross-matching to avoid immunohematological problems and interdonor incompatibility. The blood fraction plasma, which is a physiologically balanced colloidal solution that fulfills many of the requirements of a blood volume expander, cannot be safely used for this purpose. The high incidence and the risk of transmitting homologous serum hepatitis associated with plasma is so great, that its use is no longer warranted. The blood component hemoglobin, possesses osmotic activity and the ability to transport and exchange oxygen, but it has the disadvantage of rapid elimination from circulation by the renal route and through vascular walls. Hemoglobin in mammals has, therefore, a short, limited half-life, for example, about two to four hours in monkeys and dogs, respectively. These disadvantages for the substitutes make their use unacceptable. In view of the above presentation, it becomes immediately apparent that a need exists for a therapeutic product useful as a blood substitute and blood plasma expander essentially free of the tribulations associated with the prior substitutes; and, if a useful product were made available, it would represent a valuable contribution to medicine.